Project summary This project investigates whether vestibular loss in aging adults predicts hippocampal atrophy. The proposed research will be carried out within the Baltimore Longitudinal Study of Aging (BLSA), a rigorous, comprehensive longitudinal study of >800 individuals age ?60. Specifically, Aim 1 is to determine whether vestibular loss predicts hippocampal atrophy. We hypothesize that vestibular loss predicts subsequent atrophy of the CA1 subfield in the posterior hippocampus where the place cells and head direction cells are predominantly located and most modulated by vestibular input. Aim 2 is to determine whether vestibular loss predicts atrophy of the major pathways that carry vestibular input to the hippocampus. We hypothesize that vestibular loss predicts atrophy of white matter tracts between the thalamus and hippocampus (e.g. fornix), and between the vestibular cortex and hippocampus (e.g. cingulum). Moreover, our exploratory hypothesis is that vestibular loss predicts atrophy of the main thalamic nuclei that relay vestibular information from the vestibular end-organs and nuclei to the hippocampus (e.g. ventroposterior complex, ventrolateral nucleus, anterior dorsal nucleus). To accomplish these aims, we will use data from the Baltimore Longitudinal Study of Aging (BLSA). BLSA participants undergo vestibular physiologic testing and repeated brain MRI evaluations every 1-2 years. We will evaluate whether changes in vestibular function predict structural hippocampal changes over a 6-year follow-up period (2013-2019) in 80 participants. The BLSA has validated advanced approaches to measure longitudinal changes in gray matter volume and white matter tract integrity. We will also collaborate with colleagues in Computational Anatomy to apply novel methods to measure hippocampal and thalamic shape (i.e. differential atrophy) and sub-field atrophy. These methods can identify the structural basis for neurodegenerative disease with remarkable precision, such as pinpointing the earliest foci of Alzheimer?s disease pathology years before the disease manifests. At the end of this grant, we will gain knowledge about the specific hippocampal sub-fields and potentially the vestibulo-hippocampal circuits that are affected by vestibular loss in aging adults. Future studies will be directed at determining whether hippocampal changes induced by vestibular loss contribute to the onset of Alzheimer?s disease. Because effective vestibular therapies exist, results of these studies will help to determine whether vestibular treatment holds promise for Alzheimer?s disease mitigation.